Peritubular Capillaritis Research Articles

Diffuse Extent of Peritubular Capillaritis in Late Antibody-Mediated Rejection

Recently, diffuse peritubular capillaritis (ptc) has been suggested to independently predict chronic transplant injury and loss, and although the ptc score is a diagnostic criterion for antibody-mediated rejection, the utility of diffuse ptc is under debate. We evaluated the diagnostic value of ptc characteristics in this cross-sectional study including 85 biopsies of patients with donor-specific antibodies (DSA). Biopsies were reevaluated for the extent (diffuse vs focal), score and leukocytic composition in relation to DSA binding strength (mean fluorescence intensity [MFI]_max). Chronic allograft injury (transplant chronic glomerulopathy [cg] or chronic lesion score CLS]) were associated with ptc features. Peritubular capillaritis was detected in 50% (76% mononuclear ptc). Peritubular capillaritis scores 1, 2, and 3 were present in 36%, 55%, and 9%, and focal or diffuse ptc in 36% or 64%. Diffuse ptc was associated with DSA MFI_max (median: 4407 vs 2419 [focal ptc; P = 0.04] or 1946 [no ptc; P = 0.004]), cg (58% vs no ptc 24% [P = 0.02]), and higher CLS (mean: 6.81 vs 4.67 [focal ptc, P = 0.01] or 5.18 [no ptc, P = 0.001]), respectively. The association of ptc score of 2 or greater with cg was slightly better than with diffuse ptc. Diffuse ptc and ptc score of 2 or greater remained independently related to cg after adjusting for DSA_MFI_max, C4d, or previous rejection episodes, however lost their independent relation after adjusting for total microcirculation scores. Diffuse ptc was the only ptc characteristic independently related to CLS. Our results emphasize the clinical relevance of reporting diffuse ptc, which may relate to DSA binding strength and potentially to chronic graft injury.

Longitudinal evaluation of perfusion changes in acute and chronic renal allograft rejection using arterial spin labeling in translational mouse models.

To examine the longitudinal changes of renal perfusion due to acute and chronic renal allograft rejection by using arterial spin labeling (ASL) MRI in translational mouse models of isogenic and allogenic kidney transplantation (ktx). Acute rejection was induced by allogenic ktx of C57BL/6 (B6)-kidney grafts to BALB/c-recipients with prolonged cold ischemia (CIT) of 60 minutes (n = 13). To induce chronic rejection BALB/c-kidneys were transplanted into B6-recipients with short CIT of 30 minutes (n = 22). Isogenic grafts without rejection (n = 14 with prolonged, n = 9 with short CIT) and normal kidneys (n = 22) were used for comparison. Perfusion was measured on a 7T small-animal magnetic resonance imaging (MRI) scanner using flow-sensitive alternating inversion recovery (FAIR) ASL-sequences at day 1 and 6 (acute) or at week 3 and 6 (chronic) after surgery. Histological analyses of grafts included inflammation, vascular changes, and fibrosis. In the acute ktx model, ASL showed perfusion impairment in isogenic and allogenic kidney grafts. Perfusion of allografts further decreased until day 6 and remained stable in isografts without rejection (allogenic ktx 62 ± 21 vs. isogenic ktx 181 ± 39 ml/min/100g, P < 0.01). In the chronic ktx model, perfusion in isografts was similar to normal kidneys over the entire observation period. Perfusion was severely reduced in allografts compared to isografts (week 3: 28 ± 7 vs. 310 ± 46 ml/min/100g, P < 0.001, week 6: 32 ± 5 vs. 367 ± 72 ml/min/100g, P < 0.001). Histological analysis revealed severe inflammation, vascular occlusion, and rejection in allografts. Chronic rejection grafts showed endothelialitis, peritubular capillaritis, interstitial fibrosis, and tubular atrophy. ASL allows longitudinal assessment of renal perfusion impairment due to acute and chronic renal allograft rejection in translational mouse models. 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:1664-1672.

Thrombalexin: Use of a Cytotopic Anticoagulant to Reduce Thrombotic Microangiopathy in a Highly Sensitized Model of Kidney Transplantation.

Early activation of coagulation is an important factor in the initiation of innate immunity, as characterized by thrombotic microangiopathy (TMA). In transplantation, systemic anticoagulation is difficult due to bleeding. A novel "cytotopic" agent, thrombalexin (TLN), combines a cell-membrane-bound (myristoyl tail) anti-thrombin (hirudin-like peptide [HLL]), which can be perfused directly to the donor organ or cells. Thromboelastography was used to measure time to clot formation (r-time) in both rhesus and human blood, comparing TLN versus HLL (without cytotopic tail) versus negative control. Both TLN- and HLL-treated rhesus or human whole blood result in significantly prolonged r-time compared to kaolin controls. Only TLN-treated human endothelial cells and neonatal porcine islets prolonged time to clot formation. Detection of membrane-bound TLN was confirmed by immunohistochemistry and fluorescence activated cell sorter. In vivo, perfusion of a nonhuman primate kidney TLN-supplemented preservation solution in a sensitized model of transplantation demonstrated no evidence of TLN systemically. Histologically, TLN was shown to be present up to 4 days after transplantation. There was no platelet deposition, and TMA severity, as well as microvascular injury scores (glomerulitis + peritubular capillaritis), were less in the TLN-treated animals. Despite promising evidence of localized efficacy, no survival benefit was demonstrated.

Histopathologic changes in anti-angiotensin II type 1 receptor antibody-positive kidney transplant recipients with acute rejection and no donor specific HLA antibodies

ObjectiveTo determine the association of antibodies against angiotensin II type 1 receptor (AT1R Ab) and histopathologic changes seen in patients with kidney allograft rejection and negative donor specific HLA antibodies (DSA). MethodsStored sera from 27 patients who had biopsy-proven rejection in the absence of DSA were tested for AT1R Ab. Biopsy slides of all patients were re-examined and classified according to Banff 2013 criteria. Histopathologic changes were compared between AT1R positive and negative patients. Results75% of patients with positive pre-transplant AT1R Ab had antibody mediated rejection (AMR) compared to 37% of AT1R Ab-negative patients. A trend towards increased interstitial inflammation was observed in the AT1R Ab positive group (p=0.08). More patients in the AT1R Ab positive group had microcirculation inflammation (88% vs 58% with glomerulitis scores ≥1; 75% vs 58% with peritubular capillaritis scores ≥1). ConclusionIn kidney transplant recipients with rejection and no DSA, a higher incidence of AMR and worse inflammation scores are observed in the presence of positive pre-transplant AT1R antibodies.

Rejection of the Renal Allograft in the Absence of Demonstrable Antibody and Complement.

Recent literature has stressed the prominent role of antibodies in graft loss. This study was designed to assess a growing perception that T cell-mediated rejection (TCMR) is no longer clinically relevant. Five hundred forty-five renal allograft recipients over a 3-year period were screened for biopsies with: (a) TCMR including borderline change (BL), (b) negative complement protein C4 degradation fragment, and (c) absence of donor-specific antibody at time of transplant, within 30 days of the biopsy, and up to 4 measurements at later time points. These stringent requirements identified 28 "pure" cases of late TCMR/BL. Low-grade glomerulitis, peritubular capillaritis, or chronic transplant glomerulopathy were found in 9/28 (32%) biopsies. Serum creatinine showed complete short-term remission in 7/10 (70%) BL and 9/18 (50%) TCMR patients 1 month postbiopsy. Yet, both treated and untreated patients demonstrated further decline in graft function as assessed by serum creatinine and estimated glomerular filtration rate. Late TCMR seen in 7.9% of biopsies can contribute to significant deterioration of graft function in patients in whom the dominant contribution of antibody-mediated injury has been reasonably excluded. Our data also reinforce existing literature showing that microvascular lesions do not have absolute specificity for a diagnosis of antibody-mediated rejection.

Renal involvement in lysinuric protein intolerance: contribution of pathology to assessment of heterogeneity of renal lesions

Lysinuric protein intolerance (LPI) is a rare autosomal recessive disease caused by mutations in the SLC7A7 gene encoding the light subunit of a cationic amino acid transporter. Symptoms mimic primary urea cycle defects but dysimmune symptoms are also described. Renal involvement in LPI was first described in the 1980s. In 2007, it appeared that it could concern as much as 75% of LPI patients and could lead to end-stage renal disease. The most common feature is proximal tubular dysfunction and nephrocalcinosis but glomerular lesions are also reported. However, very little is known regarding histological lesions associated with LPI. We gathered every kidney biopsy of LPI-proven patients in our highly specialized pediatric and adult institution. Clinical, biological, and histological information was analyzed. Five LPI patients underwent kidney biopsy in our institution between 1986 and 2015. Clinically, 4/5 presented with proximal tubular dysfunction and 3/5 with nephrotic range proteinuria. Histology showed unspecific tubulointerstitial lesions and nephrocalcinosis in 3/5 biopsies and marked peritubular capillaritis in one child. Glomerular lesions were heterogeneous: lupus-like-full house membranoproliferative glomerulonephritis (MPGN) in one child evolved towards monotypic IgG1κ MPGN sensitive to immunomodulators. One patient presented with glomerular non-AA non-AL amyloidosis. Renal biopsy is particularly relevant in LPI presenting with glomerular symptoms for which variable histological lesions can be responsible, implying specific treatment and follow-up.

Increased Circulating T Lymphocytes Expressing HLA-DR in Kidney Transplant Recipients with Microcirculation Inflammation.

We consecutively enrolled 82 kidney transplant recipients (KTRs) with stable renal function and 24 KTRs who underwent indication biopsy to compare the histological grading of renal allografts with the activity of circulating T lymphocyte subsets and monocytes determined by flow cytometry, which were obtained at 2 weeks after kidney transplantation (KT) and at the time of indication biopsy, respectively. The sum of the scores of glomerulitis (g) + peritubular capillaritis (ptc), inflammation (i) + tubulitis (t), interstitial fibrosis (ci) + tubular atrophy (ct), and fibrointimal thickening (cv) + arteriolar hyaline thickening (ah) was used to assign a histological grade to the renal allograft samples. The frequencies of CD4+HLA-DR+/CD4+ T cells and CD8+HLA-DR+/CD8+ T cells were significantly increased in KTRs with a microcirculation inflammation (MI) sum score ≥ 1 when compared with KTRs with an MI sum score = 0 as well as stable KTRs. In these 2 subsets, only CD4+HLA-DR+/CD4+ T cells were positively correlated with MI sum scores. Analysis using the receiver operating characteristic (ROC) curve showed that antibody-mediated rejection (AMR) could be predicted with a sensitivity of 80.0% and a specificity of 94.7%, using a cutoff value of 29.6% frequency of CD4+HLA-DR+/CD4+ T cells. MI was significantly associated with an increased frequency of activated T lymphocytes expressing human leukocyte antigen-antigen D related (HLA-DR). Further studies should focus on validating the utility of circulating CD4+HLA-DR+/CD4+ T cells as a noninvasive, immunologic monitoring tool for the prediction of AMR.

Antibody-Mediated Acute Vascular Rejection of Kidney Allografts: Fifteen-Year Follow-up

BackgroundAlthough acute vascular rejection (AVR) is associated with a high risk of graft loss, it remains unclear whether AVR with accompanied cellular or humoral rejection (AHR) has dissimilar outcomes. The aim of this study was to examine the association between subtypes of AVR and graft loss. MethodsWe assessed patients who provided biopsy samples for acute allograft rejection from 1998 to 2014. To investigate distinct rejection patterns, we retrospectively assessed rejection episodes with review of graft histology as well as donor-specific anti-HLA antibodies when available. ResultsA total of 1,004 patients were biopsied and included in the main analyses, of which 259 (32.87%) had acute biopsy-proven rejection. We identified three patterns of graft rejection defined according to the presence of peritubular capillaritis (ptc): a) T-cell–mediated acute vascular rejection if ptc free; b) humoral-mediated acute vascular rejection if ptc >0; and c) T-cell–mediated rejection if vasculitis = 0 and ptc = 0 (148 [57%], 70 [27%], and 41 [16%], respectively). At 5 years, graft survival was lower among patients with ptc-vascular rejection than those with T-cell vascular rejection (72.3% vs 83.2%; P = .010). T-cell–mediated rejection without vasculitis had similar survival compared with rejection absence (89.3% vs 8 9.2%; P = .698). Multivariate analysis adjusted by age and sex showed that risk of graft loss was higher in biopsies with high scores of glomerulitis (g2-g3); vasculitis (v2-v3), capillaritis (ptc2-ptc3), or interstitial inflammation (i2-i3). However, tubulitis and C4d were not statically significant. ConclusionsWe conclude that antibody-mediated AVR involves a poorer prognosis than T-cell–mediated AVR. The presence of tubulitis does not seem to determine a poor long-term renal graft prognosis.

Clinical significance of the presence of anti-human leukocyte antigen-donor specific antibody in kidney transplant recipients with allograft dysfunction.

Background/AimsThis study investigated the clinical significance of detecting anti-human leukocyte antigen-donor specific antibody (HLA-DSA) in kidney transplant recipients (KTRs) requiring indication biopsy owing to allograft dysfunction.MethodsWe analyzed the presence of HLA-DSA in 210 KTRs who took indication biopsy. We divided these cases into two groups, HLA-DSA (+) (n = 52) and HLA-DSA (–) (n = 158) group, and compared the clinical characteristics, pathological findings, and clinical outcomes of the two groups.ResultsThe rates of retransplant, pretransplant sensitization, and HLA-mismatch were significantly higher in HLA-DSA (+) group than in HLA-DSA (–) group (p < 0.05 for each comparison). In histologic finding, all types of rejections were more frequent in the former group. Besides, scores of both the T-cell injury markers such as tubulitis, interstitial inf lammation, and vasculitis and antibody-mediated injury markers such as peritubular C4d deposition and microvascular inflammation (glomerulitis plus peritubular capillaritis) were higher in HLA-DSA (+) group (p < 0.05 for each). Notably, allograft outcomes were worse in HLA-DSA (+) group. Further, multivariate analysis showed that presence of HLA-DSA, advanced interstitial fibrosis/tubular atrophy (interstitial fibrosis plus tubular atrophy ≥ 2), and allograft rejection in biopsy were independent risk factors for allograft failure.ConclusionsThe results of this study showed that presence of HLA-DSA in a case of allograft dysfunction adversely influences allograft outcome, and its detection, irrespective of the result of the allograft biopsy, necessitates intensive monitoring and treatment.

P044 C1q status and titer of de novo donor specific antibodies are not predictors of allograft survival

De novo donor-specific antibodies ( dn DSA) that develop after renal transplantation are independent predictors of allograft loss. However, it is unknown if dn DSA C1q status or titer at the time of first detection can independently predict allograft outcomes. In 70 renal transplant recipients who developed dn DSA we performed LABScreen single antigen bead assays using: neat, neat with ethylenediaminetetraacetic acid (EDTA), three dilutions after EDTA treatment (1:16, 1:64, 1:1024) and the C1q assay (neat sera). Histologic and clinical outcomes were correlated with the C1q assay or dn DSA titer. C1q positivity correlated with dn DSA titer (p dn DSA (p dn DSA development, but did not predict T-cell mediated rejection (TCMR) or antibody mediated rejection (ABMR). De novo DSA titer correlated with glomuerulitis, interstitial inflammation, tubulitis, peritubular capillaritis, and C4d scores, and predicted TCMR (p dnDSA development or other known predictors of post-dnDSA graft loss (i.e. clinical phenotype or non-adherence) neither C1q status nor dn DSA titer were independent predictors of a composite outcome of a 50% decline in eGFR or allograft loss (Fig. 1). Therefore, at present the additional cost and time associated with these approaches is not justified in routine practise. However, in cases where a renal biopsy is not possible dn DSA titer correlates with TCMR, and AMBR, and may assist in risk stratification. Download high-res image (239KB) Download full-size image

P157 Accelerated graft loss due to non-complement fixing donor-specific antibody against a single DP epitope

Aim The clinical significance of donor-specific antibody (DSA) solely to DP antigens remains controversial. Here we report a case of accelerated graft loss attributed to DSA against a single DPB epitope which was exacerbated by the “peanut butter” phenomenon observed with the solid-phase single antigen bead (SAB) assays. Methods A 48-yo white female with history of ESRD due to hypertension received her 3rd renal transplant (TX) from a deceased donor with 5/6 ABDR mismatch and a 100% cPRA. Her other sensitizations included a pregnancy and multiple transfusions. Results Despite the presence of DSA to DPB1 ∗ 02:01 at 7100 MFI, TX was proceeded in light of clearly negative flow crossmatches (FCXM). Post-TX urine output initially improved but trended down on post-operative day (POD) 2 with elevated serum creatinine ⩾ 6 mg/dL. While SAB on POD3 indicated a decline of DP2 DSA to 4200 MFI, biopsy revealed a Banff IA rejection, with peritubular capillaritis and endothelial cell and vascular injury, suggestive of humoral components. Subsequent SAB on POD13 showed the addition of de novo DSA to B37 at 4300 MFI. Despite immediate intervention with ATG/IVIG/Rituxan/plasmapheresis, the patient developed a profound septic syndrome and a nephrectomy was performed on POD24. Allograft biopsy showed strong evidence of AMR with diffuse cortical necrosis and hemorrhage, arterial thromboses, intimal arteritis, with C4d+ in the peritubular capillaries. Epitope analysis suggested the preexisting DP DSA was in fact directed to a single epitope, 56EE, shared amongst 9 beads comprising 6 DPB1 alleles (02:01/04:02/10:01/18:01/28:01), thereby inadvertently diluting the actual DSA titer as shown on individual beads (“the peanut butter effect”). While it was not being detected by FCXM, the cumulative pre-TX MFI of the DP DSA was indeed > 65,000. Retrospective testing indicated that this DP DSA was never complement fixing, suggesting an involvement of antibody dependent cell-mediated cytoxicity. An intermediate level of anti-AT1R antibody was detected post-TX, which may have further accelerated the graft rejection process. Conclusions This case illustrates the deleterious effect of DSA solely to DP antigens. Epitope analysis may facilitate a more accurate assessment of the actual DSA titer, especially for the highly sensitized patients.

A Probabilistic Approach to Histologic Diagnosis of Antibody-Mediated Rejection in Kidney Transplant Biopsies.

Histologic diagnosis of antibody-mediated rejection (ABMR) in kidney transplant biopsies uses lesion score cutoffs such as 0 versus >0 rather than actual scores and requires donor-specific antibody (DSA); however, cutoffs lose information, and DSA is not always reliable. Using microarray-derived molecular ABMR scores as a histology-independent estimate of ABMR in 703 biopsies, we reassessed criteria for ABMR to determine relative importance of various lesions, the utility of equations using actual scores rather than cutoffs, and the potential for diagnosing ABMR when DSA is unknown or negative. We confirmed that the important features for ABMR diagnosis were peritubular capillaritis (ptc), glomerulitis (g), glomerular double contours, DSA and C4d staining, but we questioned some features: arterial fibrosis, vasculitis, acute tubular injury, and sum of ptc+g scores. Regression equations using lesion scores predicted molecular ABMR more accurately than score cutoffs (area under the curve 0.85-0.86 vs. 0.75). DSA positivity improved accuracy, but regression equations predicted ABMR with moderate accuracy when DSA was unknown. Some biopsies without detectable DSA had high probability of ABMR by regression, although most had HLA antibody. We concluded that regression equations using lesion scores plus DSA maximized diagnostic accuracy and can estimate probable ABMR when DSA is unknown or undetectable.

Anti-Angiotensin II Type 1 Receptor and Anti-Endothelial Cell Antibodies: A Cross-Sectional Analysis of Pathological Findings in Allograft Biopsies.

BackgroundThis is a cross-sectional study designed to evaluate the histologic characteristics of graft injury in the presence of anti-angiotensin II type 1 receptor antibody (AT1R-Ab) and anti-endothelial cell antibody (AECA).MethodsNon-HLA antibody testing was included in the posttransplant evaluation for 70 kidney recipients. Biopsies were performed for cause for 47 patients and as protocol for the remaining 23 patients. Biopsy-proven rejection was defined according to the Banff 2009-2013 criteria. AT1R-Ab was measured on an ELISA platform. Patients were divided into 3 groups based on AT1R-Ab levels (>17, 10-17, and <10 U/ml). AECA was evaluated using an endothelial cell crossmatch (ECXM) in patients whose HLA antibody level was insufficient to cause a positive flow cytometric crossmatch.ResultsAT1R-Ab levels were higher in patients diagnosed with antibody mediated rejection compared to those with no rejection (P = 0.004). Glomerulitis (g) and peritubular capillaritis (ptc) scores were independently correlated with increased AT1R-Ab concentrations in the presence or absence of HLA-DSA (P = 0.007 and 0.03 for g scores; p = 0.005 and 0.03 for ptc scores). Patients with a positive ECXM had higher AT1R-Ab levels compared to those with a negative ECXM (P = 0.005). Microcirculation inflammation (MCI = g + ptc score) was higher in patients with a positive ECXM and with AT1R-Ab >17 U/ml, although this did not reach statistical significance (P = 0.07).ConclusionsThe data show an association between non-HLA antibodies detected in the ECXM and AT1R ELISA and microvascular injury observed in antibody mediated rejection.

In kidney transplant recipients with BK polyomavirus infection, early BK nephropathy, microvascular inflammation, and serum creatinine are risk factors for graft loss.

Little information is available on the risk factors for graft loss in kidney transplant recipients with BK polyomavirus (BKPyV) nephropathy (BKVN) in the presence or absence of antibody-mediated rejection (AMR). We examined the risk factors for graft loss in consecutive kidney allograft recipients with biopsy-confirmed BKVN, with or without concomitant AMR. A total of 1904 kidney transplants were performed at our institution during 2005-2011. Of these, 330 (17.33%) were diagnosed with BKPyV viremia, and 69 were diagnosed with BKVN (3.6%). Eleven patients had a concomitant diagnosis of AMR. Patients with AMR were characterized by significantly higher peak panel-reactive antibody, retransplant rates, and desensitization preconditioning at the time of transplantation, as well as microvascular inflammation (MVI = glomerulitis + peritubular capillaritis), C4d score, and donor-specific antibody at the time of diagnosis (P ≤ 0.01). Treatment with plasma exchange, intravenous immunoglobulin, and cidofovir was more prevalent in this group (P ≤ 0.02). Univariate analyses assessing the risk factors for graft loss in all patients with BKVN, identified an independent association of African-American race, deceased-donor transplantation, serum creatinine (Scr), MVI, and early disease (BKVN within 6 months of transplant) with poor outcomes. Multivariate analyses retained only 3 variables: Scr >2 mg/dL (hazard ratio [HR] = 4.3, 95% confidence interval [CI] 1.9-9.7, P = 0.0004), early BKVN (HR = 2.7, 95% CI 1.3-5.3, P = 0.004), and MVI (HR = 1.8, 95% CI 1.2-2.8, P = 0.008). These observations suggest that, in patients with BK infection, early BKVN, Scr >2, and MVI are predictors of poor outcomes. Further studies are needed to determine effective treatment strategies for BKVN, with or without AMR.

Delayed Graft Function Is Associated with Microvascular Thrombosis in a Donor with Disseminated Intravascular Coagulation

Microvascular thrombosis is an uncommon pathological finding in deceased donor kidneys. It is associated with disseminated intravascular coagulation (DIC) after brain injury in the donor. Although DIC in deceased kidney donors is known to have no association with graft outcome, microvascular thrombosis with DIC in a donor can cause renal graft impairment. For this reason, some transplantation centers do not accept these kidneys. A 39-year-old female donor had a subarachnoid hemorrhage. After a short period of cardiopulmonary resuscitation, we applied extracorporeal membrane oxygenation to maintain hemodynamic stability. The laboratory data were consistent with DIC. The recipient was a 38-year-old male patient who had been undergoing hemodialysis for 7 years because of end-stage renal disease of unknown cause. Zero-time graft biopsy revealed multiple intraluminal fibrin thrombi without peritubular capillaritis. Delayed graft function occurred after transplantation, and hemodialysis was started. Graft renal biopsy was performed on the third day after transplantation. The percentage of intraglomerular fibrin thrombi had decreased, and no significant peritubular capillaritis or C4d staining was observed. The function of the transplanted kidney started to recover, and hemodialysis was discontinued on the 10th day after surgery without specific treatment. Follow-up biopsy performed 20 days after the transplantation revealed normal kidney with completely resolved fibrin thrombi. We report herein a case of microvascular thrombosis in renal allograft from a DIC donor.

The Revised (2013) Banff Classification for Antibody-Mediated Rejection of Renal Allografts: Update, Difficulties, and Future Considerations.

The Banff 2013 classification (Banff 2013) for antibody-mediated rejection (ABMR) in renal allografts represents the first major revision of the original Banff classification for ABMR that was published in 2003. The main impetus for this revision was the need to include C4d-negative ABMR, although this revised classification contains a number of additional features based on findings reported from 2007 to 2013. Since its publication, several studies have examined the validity of different aspects of Banff 2013 and compared it to earlier (2003, 2007) versions of the Banff ABMR classification. Recent evidence, albeit limited, indicates that Banff 2013 represents an improvement over the previous versions, enhancing our ability to accurately diagnose cases of acute/active and chronic active ABMR on renal allograft biopsy. Molecular studies appear to justify the threshold value of glomerulitis plus peritubular capillaritis score ≥2 required by Banff 2013 for the diagnosis of C4d-negative ABMR; however, other aspects of the classification, including its overall interobserver reproducibility, the clinical significance of the category of C4d staining without evidence of rejection, and whether surrogate markers might potentially substitute for the requirement for the presence of donor-specific antibodies, require additional investigation.

2013 Banff Criteria for Chronic Active Antibody-Mediated Rejection: Assessment in a Real-Life Setting.

Significant changes in the criteria for chronic active antibody-mediated rejection (CAABMR) were made in the Banff 2013 classification. These modifications expanded the number of patients diagnosed with CAABMR, with undetermined clinical significance. We compared the 2007 and 2013 criteria for the composite end point of death-censored graft failure or doubling of serum creatinine in 123 patients meeting the criterion related to the morphologic evidence of chronic tissue injury. In all, 18% and 36% of the patients met the 2007 and 2013 criteria, respectively. For the criterion related to antibody interaction with endothelium, only 25% were positive based on the 2007 definition compared with 82% using the 2013 definition. Cox modeling revealed that a 2013 but not a 2007 diagnosis was associated with the composite end point (adjusted hazard ratio 2.5 [95% confidence interval (CI) 1.2-5.2] vs. 1.6 [95% CI 0.7-3.8], respectively). The 2013 criterion based on both the C4d score and the glomerulitis plus peritubular capillaritis score (g+ptc) was more strongly associated with the end point than the 2007 criterion based only on C4d; however, when dissected by component, only the C4d component was significant. The association with clinical outcomes improved with the 2013 criteria. This is related to the new C4d threshold but not to the g+ptc ≥2 component.

Identifying Subphenotypes of Antibody-Mediated Rejection in Kidney Transplants.

The key lesions in antibody-mediated kidney transplant rejection (ABMR) are microcirculation inflammation (peritubular capillaritis and/or glomerulitis lesions, abbreviated "pg") and glomerular double contours (cg lesions). We used these features to explore subphenotypes in 164 indication biopsies with ABMR-related diagnoses: 137 ABMR (109 pure and 28 mixed with T cell-mediated rejection [TCMR]) and 27 transplant glomerulopathy (TG), identified from prospective multicenter studies. The lesions indicated three ABMR subphenotypes: pgABMR, cgABMR, and pgcgABMR. Principal component analysis confirmed these subphenotypes and showed that TG can be reclassified as pgcgABMR (n = 17) or cgABMR (n = 10). ABMR-related biopsies included 45 pgABMR, 90 pgcgABMR, and 25 cgABMR, with four unclassifiable. Dominating all time intervals was the subphenotype pgcgABMR. The pgABMR subphenotype presented earliest (median <2 years), frequently mixed with TCMR, and was most associated with nonadherence. The cgABMR subphenotype presented late (median 9 years). Subphenotypes differed in their molecular changes, with pgABMR having the most histologic-molecular discrepancies (i.e. potential errors). Donor-specific antibody (DSA) was not identified in 29% of pgcgABMR and 46% of cgABMR, but failure rates and molecular findings were similar to cases where DSA was known to be positive. Thus, ABMR presents distinct subphenotypes, early pg-dominant, late cg-dominant, and combined pgcg phenotype, differing in time, molecular features, accompanying TCMR, HLA antibody, and probability of nonadherence.

Immune Complex Mediated Glomerulonephritis with Acute Thrombotic Microangiopathy following Newly Detected Hepatitis B Virus Infection in a Kidney Transplant Recipient.

Hepatitis B virus (HBV) presents a risk to patients and staff in renal units. To minimise viral transmission, there are international and UK guidelines recommending HBV immunisation for patients commencing renal replacement therapy (RRT) and HBV surveillance in kidney transplant recipients. We report the case of a 56-year-old male who was immunised against HBV before starting haemodialysis. He received a deceased donor kidney transplant three years later, at which time there was no evidence of HBV infection. After a further six years he developed an acute kidney injury; allograft biopsy revealed an acute thrombotic microangiopathy (TMA) with glomerulitis, peritubular capillaritis, and C4d staining. Due to a “full house” immunoprofile, tests including virological screening were undertaken, which revealed acute HBV infection. Entecavir treatment resulted in an improvement in viral load and kidney function. HBV genotyping demonstrated a vaccine escape mutant, suggesting “past resolved” infection that reactivated with immunosuppression, though posttransplant acquisition cannot be excluded. This is the first reported case of acute HBV infection associated with immune complex mediated glomerulonephritis and TMA. Furthermore, it highlights the importance of HBV surveillance in kidney transplant recipients, which although addressed by UK guidelines is not currently practiced in all UK units.

Expanding the antibody-mediated component of plasma cell-rich acute rejection: A case series.

Renal allograft rejection is mediated by T-cells (T-cell mediated rejection) or by donor-specific antibodies (DSAs) (antibody mediated rejection, ABMR). Plasma cell-rich acute rejection (PCAR) is a unique entity due to its peculiar morphology and poor prognostic behavior. All allograft biopsies done at our center from January 2013 to October 2014 were reviewed, and seven were identified with a diagnosis of PCAR with antibody mediated rejection (ABMR). The allograft biopsies were classified as per the Banff 2007 schema. Immunohistochemistry with C4d, SV 40, CD3, CD20, CD138, kappa and lambda light chain was performed. Total 210 allograft biopsies were performed in the study period of which seven biopsies (3.3%) were diagnosed as PCAR with ABMR. All these were late ABMRs (more than 6 months) with median posttransplant duration of 17 months. The allograft biopsy showed features of PCAR along with glomerulitis, peritubular capillaritis, and positive C4d. DSA was positive in six patients. All the patients were treated with standard therapeutic measures of acute cellular rejection (ACR) and ABMR including steroids, plasma exchange, rituximab and intravenous immunoglobulins. All the patients had persistent graft dysfunction or graft loss on follow-up.